Extended release pharmaceutical compositions

ABSTRACT

The present invention provides extended release pharmaceutical compositions structured for once a day administration comprising skeletal muscle relaxant such as cyclobenzaprine or its pharmaceutically acceptable salt thereof that extends the release of the drug under in-vitro conditions for at least 8 to 12 hours. The invention also provides process for the preparation of such structured compositions.

PRIORITY

This application claims benefit of international applicationPCT/IB2010/0001229, filed May 20, 2010, and Indian application1287/MUM/2009, filed on May 22, 2009, the contents of all of which areincorporated by reference in their entireties herein.

FIELD OF THE INVENTION

This invention relates to extended release pharmaceutical compositionscomprising skeletal muscle relaxant such as cyclobenzaprine or itspharmaceutically acceptable salt thereof and a process for preparationthereof.

BACKGROUND OF THE INVENTION

Cyclobenzaprine Hydrochloride, a skeletal muscle relaxant is currentlyavailable as immediate release tablets containing 5 mg or 10 mg of theactive and also as extended release capsules containing 15 mg or 30 mgof the active. Immediate release tablets are recommended to beadministered three times a day to achieve relief from muscle spasm.Administration of such tablets three times a day is a major complianceissue especially in elderly patients. To substantially enhance patientcompliance, it is desirable to provide cyclobenzaprine hydrochloride inextended release dosage form for once a day administration.

U.S. Pat. No. 7,387,793, U.S. Pat. No. 7,544,372, US Patent Application2008/0124398, US Patent Application 2009/0017126, US Patent Application2009/0017127 and US Patent Application 20090148532 disclosemulti-particulate pharmaceutical dosage forms of a skeletal musclerelaxant for once a day administration comprising a population ofextended release beads. These extended release beads comprise:

-   -   an active-containing core particle comprising a skeletal muscle        relaxant selected from the group consisting of cyclobenzaprine,        pharmaceutically acceptable salts or derivatives thereof and        mixtures thereof; and    -   an extended release coating comprising a water insoluble polymer        membrane surrounding the said core, wherein the membrane        comprises a water insoluble polymer and a plasticizer.

The dosage form exhibits the following in-vitro dissolution profile inUSP apparatus 2 (paddles @ 50 rpm) in 900 ml of 0.1N HCl at 37° C.:

-   -   not more than 40% of the total active is released at 2 hour;    -   from about 40-65% of the total active is released at 4 hour;    -   from about 60-85% of the total active is released at 8 hour.

OBJECTS OF THE INVENTION

The object of the invention is to provide extended releasepharmaceutical compositions structured for once a day administrationcomprising skeletal muscle relaxant such as cyclobenzaprine or itspharmaceutically acceptable salt thereof that exhibits in-vitro drugrelease profile for at least 8 to 12 hours.

It is another object of the invention to provide the said structuredcompositions comprising cyclobenzaprine or its pharmaceuticallyacceptable salt thereof, wherein the composition comprises of a core, alayer comprising of one or more extended release agents, and the saiddrug either in the extended release layer or in between the core and theextended release layer or in the core.

It is yet another object of the invention to provide the abovecompositions in the form of pellets capable of being filled in capsules.

It is yet another object of the invention to provide extended releasecompositions which would substantially minimize the incidence of dosedumping.

It is yet another object of the invention to provide process for thepreparation of extended release pharmaceutical compositions comprisingcyclobenzaprine or its pharmaceutically acceptable salts thereof thatexhibits in-vitro drug release profile for at least 8 to 12 hours.

DESCRIPTION OF THE INVENTION

Description of Figures

FIGS. 1(a), 1(b), and 1(c) illustrate the manner in which thecompositions of the present invention can be structured.

The present invention provides extended release pharmaceuticalcompositions structured for once a day administration comprisingskeletal muscle relaxant such as cyclobenzaprine or it'spharmaceutically acceptable salt thereof that extends the release of thedrug under in-vitro conditions for at least 8 to 12 hours.

Such structured compositions comprising skeletal muscle relaxant such ascyclobenzaprine or its pharmaceutically acceptable salt thereofcomprises of:

-   -   a) a core;    -   b) a layer comprising of one or more extended release agents;        and    -   c) the said cyclobenzaprine or its pharmaceutically acceptable        salt thereof is either (i) in the extended release layer,        or (ii) in between the core and the extended release layer,        or (iii) in the core.

Structuring the Composition:

In a preferred embodiment of the invention, the extended releasepharmaceutical compositions comprise of:

-   -   a) inert core;    -   b) said inert core being coated with a matrix comprising        cyclobenzaprine or its pharmaceutically acceptable salt thereof        such as cyclobenzaprine HCl and one or more extended release        agents.

In another preferred embodiment of the invention, the extended releasepharmaceutical compositions comprise of:

-   a) inert core;-   b) said inert core being coated with a matrix comprising    cyclobenzaprine or its pharmaceutically acceptable salt thereof such    as cyclobenzaprine HCl and one or more extended release agents and    one or more plasticizer.

As shown in FIG. 1(a), the composition is structured to form a matrixthat comprises of an inert core (i), the inert core being coated with alayer (ii) comprising of cyclobenzaprine or its pharmaceuticallyacceptable salt thereof such as cyclobenzaprine hydrochloride and one ormore extended release agents.

The process for the preparation of composition to obtain the structureas shown in FIG. 1(a) comprises steps of:

-   i. providing an inert core;-   ii. applying a layer comprising of cyclobenzaprine or its    pharmaceutically acceptable salt thereof such as cyclobenzaprine    hydrochloride, one or more extended release agents and optionally at    least one additive selected from binder, anti-tack agent,    plasticizer, diluent, or mixtures thereof on the inert core to    obtain extended release pellets.

Creation of the said layer on the inert core comprises steps of:

-   -   i. dispersing and/or dissolving cyclobenzaprine or its        pharmaceutically acceptable salt thereof such as cyclobenzaprine        hydrochloride in a solvent selected from water, alcohol, organic        solvent, or mixtures thereof to obtain drug dispersion or        solution;    -   ii. dispersing and or dissolving one or more extended release        agents in a solvent selected from water, alcohol, organic        solvent, or mixtures thereof to obtain dispersion or solution;    -   iii. mixing dispersion or solution of step (ii) with drug        dispersion or solution of step (i)    -   iv. optionally adding at least one additive selected from        binder, anti-tack agent, plasticizer, diluent, or mixtures        thereof to dispersion or solution of step (iii);    -   v. spraying the resulting dispersion or solution on inert cores        to obtain extended release pellets;    -   vi. drying and sizing the extended release pellets.

In one of the embodiments of the invention, the extended releasepharmaceutical compositions comprises of:

-   a) inert core;-   b) first layer comprising of cyclobenzaprine or its pharmaceutically    acceptable salt thereof such as cyclobenzaprine HCl on the inert    core; and-   c) second layer comprising of one or more extended release agents on    the first layer; wherein the said second layer does not contain    plasticizer.

As shown in FIG. 1(b), the compositions are structured to provide aninert core (i), first layer (ii) comprising of cyclobenzaprine or itspharmaceutically acceptable salt thereof such as cyclobenzaprinehydrochloride on the inert core and second layer (iii) comprising one ormore extended release agents on the first layer, wherein the said secondlayer does not contain plasticizer.

The process for the preparation of composition to obtain the structureas shown in FIG. 1(b) comprises steps of:

-   -   a) providing an inert core;    -   b) creating a first layer comprising of cyclobenzaprine or its        pharmaceutically acceptable salt thereof such as cyclobenzaprine        hydrochloride on the inert core to obtain drug core; and    -   c) creating a second layer comprising of one or more extended        release agents on the first layer to obtain extended release        pellets;        wherein the second layer does not contain plasticizer.

Creation of the said first layer on the inert core comprises steps of:

-   i. dispersing and or dissolving cyclobenzaprine or its    pharmaceutically acceptable salt thereof such as cyclobenzaprine    hydrochloride in a solvent selected from water, alcohol, organic    solvent, or mixtures thereof to obtain drug dispersion or solution;-   ii. optionally dispersing and or dissolving at least one additive    selected from binder, diluent, plasticizer, anti-tack agent, or    mixtures thereof in a solvent selected from water, alcohol, organic    solvent, or mixtures thereof;-   iii. mixing dispersion or solution of step (ii) with drug dispersion    or solution of step (i);-   iv. spraying the resulting dispersion or solution of step (iii) on    inert cores to obtain drug cores;-   v. drying and sizing the drug cores.

Creation of the second layer (extended release layer) on the drug corecomprises steps of:

-   i. dispersing and or dissolving one or more extended release agents    in a solvent selected from water, alcohol, organic solvent, or    mixtures thereof to obtain dispersion or solution;-   ii. optionally adding at least one additive selected from anti-tack    agent, diluents, or mixtures thereof;-   iii. spraying the resulting dispersion or solution on drug pellets    to obtain extended release pellets;-   iv. drying and sizing the extended release pellets.

In another embodiment of the invention, the extended releasepharmaceutical compositions comprises of:

-   a) a core comprising of cyclobenzaprine or its pharmaceutically    acceptable salt thereof such as cyclobenzaprine HCl;-   b) a layer comprising of or more extended release agents coated on    the core; wherein the said layer does not contain plasticizer.

As shown in FIG. 1(c), the compositions are structured to form a core(i) comprising of cyclobenzaprine or its pharmaceutically acceptablesalt thereof such as cyclobenzaprine hydrochloride, the core beingcoated with a layer (ii) comprising of one or more extended releaseagents, wherein the said coating layer does not contain plasticizer.

The process for the preparation of the compositions as shown in FIG. 1(c) comprises steps of:

-   i. providing a matrix core comprising of cyclobenzaprine or its    pharmaceutically acceptable salt thereof such as cyclobenzaprine    hydrochloride and at least one additive selected from binder,    anti-tack agent, plasticizers, diluents, or mixtures thereof;-   ii. creating a layer comprising of one or more extended release    agents on the matrix core to obtain extended release pellets, the    layer optionally comprises of at least one additive selected from    anti-tack agent, diluents, or mixtures thereof, wherein the said    layer does not contain plasticizer.

Preparation of the Said Matrix Core Comprises Steps of:

-   i. mixing cyclobenzaprine or its pharmaceutically acceptable salt    thereof such as cyclobenzaprine hydrochloride with at least one    additive selected from binder, anti-tack agent, plasticizers,    diluents, or mixtures thereof in a mixer to obtain drug mixture;-   ii. granulating drug mixture with a granulating solvent selected    from water, alcohol, organic solvent, or mixtures thereof to obtain    the granules;-   iii. extruding the granules in an extruder to obtain the extrudates;-   iv. spheronizing the extrudates in the spheronizer to obtain the    matrix core;-   v. drying and sizing the matrix core.

Creation of the said extended release layer on the said matrix corecomprises steps of:

-   i. dispersing and or dissolving one or more extended release agents    in a solvent selected from water, alcohol, organic solvent, or    mixtures thereof to obtain dispersion or solution;-   ii. optionally adding at least one additive selected from anti-tack    agent, diluents, or mixtures thereof;-   iii. spraying the resulting dispersion or solution on the matrix    cores to obtain extended release pellets;-   iv. drying and sizing the extended release pellets.

Cyclobenzaprine salt is the addition salt of cyclobenzaprine with aninorganic acid such as hydrochloric, hydrobromic, phosphoric, nitric, orsulphuric or of organic acid such as tartaric, acetic, propionic,hydroxyacetic, oxaloacetic, oxalic, pyruvic, succinic, malic, malonic,fumaric, lactic, glutaric, maleic, sulphonic, benzenesulphonic, and thelike. The preferred cyclobenzaprine salt is cyclobenzaprine HCl and isusually administered in the dose of 15 mg and 30 mg strength.

There is no limitation on the particle sizes of cyclobenzaprine HCl usedin the invention. However, the particle size of cyclobenzaprine HClranges from 0.1 microns to 1000 microns, preferably from 0.5 micron to500 microns, more preferably from 1 micron to 200 microns and mostpreferably from 2 microns to 100 microns.

Cyclobenzaprine HCl in the composition is from 0.01% to 50% by weight,preferably from 0.05% to 40%, more preferably from 0.1% to 25%, and mostpreferably from 2.5% to 15% by weight of the composition.

Extended release agent is selected from the group of cellulose ethers,cellulose esters polymethacrylates, wax, fatty acid, fatty alcohol,polyalkylene glycol, or mixtures thereof. However, any other suitableagent(s) that extends the release of cyclobenzaprine HCl from the dosageform may also be used.

Representative examples of such agent includes ethylcellulose powder,aqueous dispersion of ethylcellulose (such as SURELEASE®, AQUACOAT® ECD30) hydroxypropylcellulose, hydroxypropylmethylcellulose,hydroxyethylcellulose, carboxymethylcellulose, sodiumcarboxymethylcellulose, calcium carboxymethylcellulose, methylcellulose,cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate,hydroxypropylmethylcellulose acetate succinate, cellulose acetatebutyrate, cellulose acetate trimellitate, cellulose acetate, polyvinylalcohol, polyvinyl acetate (such as KOLLICOAT SR 30D), povidone,polyethylene glycol, cetyl alcohol, stearyl alcohol, bees wax, carnaubawax, stearic acid, vinyl pyrrolidone-vinyl acetate copolymer (such asKOLLIDON VA 64, KOLLIDON SR), dimethylaminoethyl methacrylate and otherneutral methacrylic acid esters (such as Eudragit E), methacrylic acidcopolymers type A (such as Eudragit L), methacrylic acid copolymers typeB (such as Eudragit S), methacrylic acid copolymers type C (such asEudragit L 30D 55), ammoniomethacrylate copolymers (such as Eudragit RL,Eudragit RS), neutral copolymer of polymethacrylic acid ester (Such asEudragit NE 30D), or mixtures thereof.

Mixtures of extended release agents are generally used in the ratio of1:0.05 to 0.05:1, preferably in the ratio of 1:0.15 to 0.15:1, morepreferably in the ratio of 1:0.3 to 0.3:1, and most preferably in theratio of 1:0.5 to 0.5:1.

These extended release agents, in general, are available in variousviscosity grades. For example hydroxypropylmethylcellulose is availablein viscosity grade of 5 cps, 6 cps, 15 cps, 100 cps, 4000 cps, 15000 cpsand 100000 cps. Similarly, ethyl cellulose powder is available inviscosity grade of 3 cps, 5 cps, 7 cps, 10 cps, 20 cps, 45 cps, 50 cpsand 100 cps. Such agents may be used alone or in mixture i.e. mixture oftwo or more different viscosity grade. For example, extended releaselayer may comprise of mixture of ethyl cellulose (10 cps) and ethylcellulose (45 cps). Such mixtures are generally used in the ratio of1:0.05 to 0.05:1, preferably in the ratio of 1:0.15 to 0.15:1, morepreferably in the ratio of 1:0.3 to 0.3:1, and most preferably in theratio of 1:0.5 to 0.5:1.

The extended release agent in the composition is from 0.5% to 90% byweight, preferably from 1% to 75%, more preferably from 2.5% to 60%,most preferably from 5% to 50% by weight of the composition.

The extended release agent in the composition is from about 50% to about90% by weight of the matrix, preferably from about 65% to about 85% byweight of the matrix

Plasticizer is selected from the group of triacetin, triethylcitrate,tributyl citrate, polyethylene glycol, acetyltribytylcitrate, miglyol,hydrogenated oils, propylene glycol, acetyltriethylcitrate, polysorbate,castor oil, oleic acid, dibutylsebacate, diethylphthalate, acetylatedmono- and di-glycerides, or mixtures thereof.

Plasticizer in the composition is from 0.1% to 30% by weight, preferablyfrom 0.5% to 20%, more preferably from 1% to 10%, and most preferablyfrom 1.5% to 5% by weight of the composition.

The inert core used in the composition is non-pareil seeds or sugarsphere or any other suitable inert material. Examples of such materialinclude sugar, starch, cellulose, microcrystalline cellulose, resin,glass beads, or mixtures thereof. The average particle size of inertcore in the present invention is from about 150 microns to about 2000microns, preferably from about 250 microns to about 1000 microns, morepreferably from about 350 microns to about 850 microns, and mostpreferably from about 500 microns to about 600 microns.

Inert core in the composition is from 15% to 80% by weight, preferablyfrom 25% to 75%, more preferably from 30% to 60%, and most preferablyfrom 40% to 50% by weight of the composition.

Diluent is selected from microcrystalline cellulose, starch,pregelatinized starch, starch 1500, cellulose, sucrose, lactose,glucose, dextrose, mannitol, sugar, cross linked povidone, sodium starchglycolate, croscarmellose sodium, croscarmellose potassium,croscarmellose calcium, monobasic sodium phosphate, dibasic sodiumphosphate, tribasic sodium phosphate, calcium phosphate, dibasic calciumphosphate, tribasic calcium phosphate, calcium sulfate, calciumcarbonate, or mixtures thereof.

Diluent in the composition is from 5% to 95% by weight, preferably from20% to 90%, more preferably from 35% to 80%, most preferably from 50% to70% by weight of the composition.

Binder is selected from xanthan gum, guar gum, acacia, tragacanth,gelatin, carrageenan polyvinylpyrrolidone, carbomer, locust bean gum,karaya gum, copovidone, agar, hydroxypropylmethylcellulose,hydroxypropylcellulose, hydroxyethylcellulose, polyethylene oxide,sodium carboxymethylcellulose, chitosan, sodium alginate, or mixturesthereof.

Binder in the composition is from 0.1% to 30% by weight, preferably from0.5% to 20%, more preferably from 1% to 10%, and most preferably from1.5% to 5% by weight of the composition.

Anti-tack agent is selected from talc, colloidal silicon dioxide,glyceryl monostearate, sodium benzoate, sodium lauryl sulfate, waxes,glyceryl behenate, stearic acid, magnesium stearate, calcium stearate,sodium stearyl fumarate, or mixtures thereof.

Anti-tack agent in the composition is from 0.1% to 30% by weight,preferably from 0.5% to 20%, more preferably from 1% to 10%, and mostpreferably from 1.5% to 5% by weight of the composition.

The solvent is selected from water, alcohol, organic solvent, ormixtures thereof. Examples of such solvent include methanol, ethanol,isopropanol, dichloromethane, acetone, halogenated hydrocarbon,ethylmethylketone, or mixtures thereof.

The pharmaceutical composition of the present invention comprises ofCyclobenzaprine or its pharmaceutically acceptable salt thereof such asCyclobenzaprine HCl and one or more agents for extended release thatexhibits in-vitro drug release for at least 8 to 12 hours.

Extended release compositions comprising Cyclobenzaprine hydrochloridewhen analyzed in-vitro in USP apparatus 2, in 0.1N HCl exhibits in-vitrodissolution profile of:

-   -   at least 5% of cyclobenzaprine HCl at 1^(st) hour;    -   at least 30% of cyclobenzaprine HCl at 4^(th) hour;    -   at least 50% of cyclobenzaprine HCl at 8^(th) hour;    -   at least 60% of cyclobenzaprine HCl at 16^(th) hour.

Preferably, extended release compositions comprising Cyclobenzaprinehydrochloride when analyzed in-vitro in USP apparatus 2, in 0.1N HClexhibits in-vitro dissolution profile of:

-   -   from 5% to 50% of cyclobenzaprine HCl at 1^(st) hour;    -   from 30% to 80% of cyclobenzaprine HCl at 4^(th) hour;    -   from 50% to 100% of cyclobenzaprine HCl at 8^(th) hour;    -   at least 75% of cyclobenzaprine HCl at 16^(th) hour.

Extended release pellets comprising cyclobenzaprine HCl complying withthe desired dissolution profile are filled in empty hard gelatin capsuleto delivery therapeutic effective amount of cyclobenzaprine HCl.

The invention further provides non-limiting examples.

Example 1 Preparation of Extended Release Pellets

-   a) Cyclobenzaprine HCl (30 g) was dissolved in purified water    (100 g) to obtain drug solution;-   b) Eudragit L 100 (75 g) was dissolved in the mixture of acetone    (300 g) and water (30 g);-   c) Eudragit RSPO (75 g) was dissolved in acetone (160 g);-   d) The solutions obtained in step a, step (b), and step (c) were    mixed and the resulting solution was sprayed on was sprayed on inert    core (20-25 mesh ASTM) (150 g) in fluid bed bottom spray processor    with inlet air temperature of about 20° C. to about 80° C., outlet    air temperature of about 20° C. to about 60° C., atomization air    pressure of about 0.5-3.5 bars, fluidization flap open from about    10% to about 90% w/w to obtain extended release pellets;-   e) Extended release pellets were dried in fluid bed bottom spray    processor to arrive at the moisture content of less than 5% w/w,    preferably less than 3% w/w, and more preferably less than 2% w/w;-   f) The dried pellets were sized, optionally lubricated with purified    talc and were filled in empty hard gelatin capsule.

Example 2 Preparation of Extended Release Pellets

-   a) Cyclobenzaprine HCl (30 g) was dissolved in purified water to    obtain drug solution;-   b) Polyethylene glycol 6000 (8 g) was added to the drug solution of    step a) and stirred to obtain clear solution;-   c) Ethyl cellulose (45 cps) (67.5 g) was dispersed in water to    obtain dispersion;-   d) Isopropanol was added to dispersion of step (c) and stirred to    obtain clear solution;-   e) Kollidon SR (15 g) was added to the solution of step (d) and    stirred to obtain clear solution;-   f) The solution obtained in step (b) was mixed with the solution    obtained in step (e) and the resulting solution was sprayed on sugar    sphere (30-35 mesh ASTM) (80 g) in fluid bed bottom spray processor    with inlet air temperature of about 20° C. to about 80° C., outlet    air temperature of about 20° C. to about 60° C., atomization air    pressure of about 0.5-3.5 bars, fluidization flap open from about    10% to about 90% w/w to obtain extended release pellets;-   g) Extended release pellets were dried in fluid bed bottom spray    processor to arrive at the moisture content of less than 5% w/w,    preferably less than 3% w/w, and more preferably less than 2% w/w;-   h) The dried pellets were sized, lubricated with purified talc    (1.5 g) and were filled in empty hard gelatin capsule.

Example 3 Preparation of Extended Release Pellets

-   a) Cyclobenzaprine HCl (30 g) was dissolved in purified water to    obtain drug solution;-   b) Ethyl cellulose (10 cps) (67.5 g) and ethyl cellulose (45 cps)    (15 g) were added to the drug solution of step (a) to obtain    dispersion;-   c) Isopropanol was added to the dispersion of step (b) and stirred    to obtain clear solution;-   d) Diethyl phthalate (4 g) was added to the solution of step (c) and    the resulting solution was sprayed on inert core (40-60 mesh ASTM)    (123.5 g) in fluid bed bottom spray processor with inlet air    temperature of about 20° C. to about 80° C., outlet air temperature    of about 20° C. to about 60° C., atomization air pressure of about    0.5-3.5 bars, fluidization flap open from about 10% to about 90% w/w    to obtain extended release pellets;-   e) Extended release pellets were dried in fluid bed bottom spray    processor to arrive at the moisture content of less than 5% w/w,    preferably less than 3% w/w, and more preferably less than 2% w/w,-   f) The dried pellets were sized, lubricated with purified talc and    were filled in empty hard gelatin capsule.

Example 4 Preparation of Matrix Cores

-   a) Cyclobenzaprine HCl (30 mg/unit), microcrystalline cellulose pH    101 (100 mg/unit) glyceryl monostearate (50 mg/unit) and Kollidon SR    (50 mg) were mixed to obtain drug mixture;-   b) Drug mixture was granulated with the solution of sodium    carboxymethylcellulose 7MF (2 mg) in water to obtain granules.-   c) The granules were extruded and spheronized to obtain matrix core.-   d) The matrix cores were dried and sized.

Example 5 Preparation of Drug Cores

-   a) Cyclobenzaprine hydrochloride (30 mg/unit) was dissolved in the    mixture of water and isopropanol.-   b) Colloidal silicon dioxide (6.02 mg/unit) and iron oxide yellow    (0.19 mg/unit) were added to the above solution to obtain    dispersion;-   c) The dispersion was sprayed on inert cores (116.27 mg/unit) (18-20    mesh ASTM) in fluid bed bottom spray processor with inlet air    temperature of about 20° C. to about 80° C., outlet air temperature    of about 20° C. to about 60° C., atomization air pressure of about    0.5-3.5 bars, fluidization flap open from about 10% to about 90% w/w    to obtain drug cores.-   d) The resulting drug cores were dried and sized.

Example 6 Preparation of Extended Release Pellets

The matrix cores of example 4 or the drug cores of example 5 were coatedwith extended release layer comprising ethyl cellulose 10 cps (4.7% byweight of the composition) to obtain extended release pellets. Theseextended release pellets were dried sized lubricated and filled incapsule.

Extended release compositions comprising cyclobenzaprine hydrochloride(examples 1 to 6) when analyzed in-vitro in USP apparatus 2, in 0.1N HCl(900 ml) exhibits in-vitro dissolution profile of:

-   -   from 10% to 38% of cyclobenzaprine HCl at 1^(st) hour;    -   from 33% to 68% of cyclobenzaprine HCl at 4^(th) hour;    -   from 68% to 81% of cyclobenzaprine HCl at 8^(th) hour;    -   from 79 to 88% of cyclobenzaprine HCl at 16^(th) hour.

STATEMENT OF PREFERRED EMBODIMENTS OF THE INVENTION

While the invention has been described with respect to preferredembodiments, those skilled in the art will readily appreciate thatvarious changes and/or modifications can be made to the inventionwithout departing from the spirit or scope of the invention as definedby the appended claims.

1.-11. (canceled)
 12. An extended release capsule compositioncomprising: a. an inert core; b. said inert core being coated with amatrix comprising cyclobenzaprine or a pharmaceutically acceptable saltthereof and one or more extended release agents, wherein the one or moreextended release agents comprise about 50% to about 90% by weight of thesaid matrix.
 13. The composition as claimed in claim 1 wherein the inertcore comprises about 15% to about 80% by weight of the composition. 14.The composition as claimed in claim 1 wherein the pharmaceuticallyacceptable cyclobenzaprine salt is cyclobenzaprine hydrochloride. 15.The composition as claimed in claim 3 comprising cyclobenzaprinehydrochloride from 0.01% to 50% by weight of the composition.
 16. Thecomposition as claimed in claim 1 wherein the one or more extendedrelease agents comprise ethyl cellulose, hydroxypropyl methylcellulosephthalate, hydroxypropyl methylcellulose acetate succinate, celluloseacetate, polyvinyl alcohol, polyvinyl acetate, cetyl alcohol, stearylalcohol, bees wax, carnauba wax, stearic acid, vinyl pyrrolidone-vinylacetate copolymer, dimethylaminoethyl methacrylate and other neutralmethacrylic acid esters, methacrylic acid copolymers type A, methacrylicacid copolymers type B, methacrylic acid copolymers type C,ammoniomethacrylate copolymers, neutral copolymer of polymethacrylicacid ester or mixtures thereof.
 17. The composition as claimed in claim1, wherein the one or more extended release agents comprise about 65% toabout 85% by weight of the matrix.
 18. The composition as claimed inclaim 1 wherein the one or more extended release agent comprises about5% to about 50% by weight of the composition.
 19. The composition asclaimed in claim 1 wherein the matrix comprises cyclobenzaprine or apharmaceutically acceptable salt thereof and two or more extendedrelease agents.
 20. The composition as claimed in claim 8 wherein thematrix comprises two or more extended release agents in the ratio of1:0.05 to 0.05:1.
 21. The composition as claimed in claim 1 wherein thematrix consists essentially of cyclobenzaprine or a pharmaceuticallyacceptable salt thereof and one or more extended release agents.
 22. Thecomposition as claimed in claim 1, wherein the matrix further comprisesone or more plasticizers.
 23. The composition as claimed in claim 10,wherein the plasticizer comprises triacetin, triethylcitrate, tributylcitrate, polyethylene glycol, acetyltribytylcitrate, miglyol,hydrogenated oils, propylene glycol, acetyltriethylcitrate, polysorbate,castor oil, oleic acid, dibutylsebacate, diethylphthalate, acetylatedmono- and di-glycerides, or a mixture thereof.
 24. The composition asclaimed in claim 1, wherein the composition further comprises at leastone pharmaceutically acceptable additive comprising a binder, diluent,anti-tack agent, or mixtures thereof.
 25. The composition as claimed inclaim 1 when analyzed in-vitro in 0.1N hydrochloric acid using USPapparatus 2 (900 mL, 37° C.), exhibits a dissolution of 5% to 50% ofcyclobenzaprine or its pharmaceutically acceptable salt thereof, at 1hour.
 26. A process for the preparation of extended release compositionof claim 1, wherein the process comprises steps of: a. dispersing and/ordissolving cyclobenzaprine or a pharmaceutically acceptable salt thereofin a solvent comprising water, alcohol, organic solvent, or a mixturethereof; b. dispersing and/or dissolving one or more extended releaseagents in a solvent comprising water, alcohol, organic solvent, or amixture thereof; c. mixing the dispersion or solution of step b. withthe dispersion or solution of step a.; d. optionally adding at least oneadditive comprising a binder, diluent, surfactant, plasticizer,anti-tack agent, lubricants, or a mixture thereof to dispersion of stepc.; e. spraying the resulting dispersion or solution, on inert cores toobtain extended release pellets; f. drying and sizing the extendedrelease pellets; and, g. filling the extended release pellets into acapsule.